Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning and addiction. Striatal Synaptic Plasticity and Drugs of Abuse We have continued our examination of changes in long-lasting striatal synaptic plasticity following in vivo exposure to drugs of abuse. These studies are carried out with electrophysiological recording in brain slices following the in vivo treatment. Our previous findings indicated that exposure to ethanol for 2-4 weeks in vivo led to a decrease in a form of long-term synaptic depression (LTD) that is initiated by activation of metabotropic glutamate receptor type 2 (mGluR2) on glutamatergic afferents to the dorsolateral striatum (DLS). In addition to these receptors, LTD can be induced by activation of several other receptor subtypes that signal through Gi/o-type G-proteins (including mu and delta opiate receptors and CB1 cannabinoid receptors). It appears that these forms of LTD are expressed presynaptically as a decrease in the probability of glutamate release. Several of these forms of Gi/o-coupled receptor-induced LTD are lost after chronic alcohol exposure in mice. Our current working hypothesis is that chronic exposure to ethanol and other drugs of abuse results in changes in receptors downstream signaling that interferes with Gi/o-mediated LTD in DLS. Loss of this synaptic depression would result in stronger cortical drive onto the projection neurons of the DLS. Given the role of the DLS in habit formation, the net effect of these drug actions on LTD could be the promotion of habitual drug seeking and taking. We are also using optogenetic techniques to examine synapses in the striatum made by afferents from identified cortical and thalamic regions. We observe mGluR2-induced LTD at both corticostriatal and thalamostriatal glutamatergic synapses onto striatal medium spiny neurons. This analysis will allow us to determine what forms of Gi/o-mediated LTD occur at which synapses both under control conditions and following in vivo ethanol exposure. We are also exploring how neurotransmitters and their receptors (including targets for drugs of abuse) contribute to long-term potentiation (LTP) at striatal synapses. Working with the laboratory of Dr. Avrama Blackwell at George Mason University we have characterized the contribution of dopamine and kappa opiate receptors to LTP induction. We find that theta-burst pattern afferent stimulation reliably induces LTP at glutamatergic synapses onto striatal medium spiny neurons (MSNs). Induction of this LTP requires dopamine activation of D1-type receptors. Optogenetic activation of the MSNs that express D1 receptors prevents LTP induction if given during theta-burst stimulation. This suppression of LTP appears to involve release of the opiate neuropeptide dynorphin and activation of Kappa opiate receptors (KORs). We find that dopamine release is inhibited by this optogenetic stimulation, in a manner that involves KORs. Thus, the KOR control of LTP induction most likely results from loss of the D1 activation needed for LTP induction. Psychoactive drugs such as Salvinorin A act via KORs, and KOR expression and function is altered by drugs of abuse including alcohol. Thus, this KOR mechanism for suppression of LTP could contribute to chronic drug effects and drug-induced behaviors. Ethanol Inhibition of Specific Neurons in the Globus Pallidus The Globus Pallidus external segment (GPe) is an important basal ganglia subregion that controls movement and is the target of therapies for movement disorders. Little is known about the effects of ethanol in this brain region, and the possible contributions of these effects to the movement impairing effects of this abused drug. Our brain slice electrophysiological experiments have revealed that ethanol inhibits the activity of a subclass of neurons in the GPe. This inhibition occurs at concentrations in the low intoxicating to highly intoxicating range. The ethanol-sensitive neurons are characterized by low action potential firing rates, expression of the Npas1 and/or Lhx6 transcription factors, and projections to the striatum. We have further discovered that the inhibition of GPe neuronal activity by ethanol is prevented by blockers of the high-conductance, calcium- and voltage-activated BK type potassium channel. Furthermore, ethanol appears to enhance the probability of opening and open time of BK channels on these neurons. These findings identify molecular and cellular mechanisms underlying a change in basal ganglia circuit function that could have important consequences for the function of the entire circuit. Ongoing experiments are assessing how ethanol affects these GPe neurons in vivo, and how this ethanol effect contributes to intoxication and chronic effects of ethanol.